The facility to control the release profile of anti-microbial or other active agents from compositions and materials is critical to their effectiveness to combat infection or contamination.
The initial rate and half-life of an active agent's release may be important factors in the efficacy of a material or composition. In addition, the facility to initiate or stimulate release of an active agent or a combination or agents by changing environmental factors can also play a vital role, e.g. by enabling targeted release of active agents.
Nitric oxide (NO) is a small molecule with anti-microbial properties and which has drawn considerable interest since it is also important in a range of biological processes. It is a vasodilator that increases blood flow through arteries and veins, and is also an important factor in controlling platelet adhesion and aggregation. It also plays a crucial role in the immune system. Much is now known about the mode of action of nitric oxide and it is clear that it has enormous potential in medicine and biotechnology in both in vivo and ex vivo applications.
The controlled delivery of nitric oxide may be important in therapy. For example, nitric oxide can prevent thrombosis and restenosis following balloon angioplasty and stent insertion in blocked arteries (International Patent Application WO 95/24908). The delivery of nitric oxide to the skin may also have therapeutic benefits for patients with peripheral circulatory problems which can occur in conditions such as arthritis and Raynaud's syndrome. Nitric oxide also plays a part in wound healing and angiogenesis, and delivery of nitric oxide to wounds can be beneficial when healing is slow which can occur, for example, in elderly patients (M. Shabani et al, Enhancement of wound repair with a topically applied nitric oxide-releasing polymer Wound repair and regeneration, 4, 353, 1996 and S. Frank H. Kampfer, C. Wetzler, J. Pfeilschifer, Nitric oxide drives skin repair: Novel functions of an established mediator Kidney International, 61, 882, 2002).
However, the delivery of nitric oxide to the desired area, and in the required optimum dose is often difficult because nitric oxide is a gas. Delivery of nitric oxide is difficult in both ex vivo e.g. biotechnology applications and in vivo e.g. medical applications.
Various methods of nitric oxide delivery are known such as
(a) molecules which release NO spontaneously;
(b) molecules which are metabolised to give NO;
(c) molecules that release NO on photoactivation;
(d) release of NO from polymers and polymer coatings;
(e) Release of NO from zeolites and metal organic frameworks (MOFs)
The class (a) of molecules include nitric oxide nucleophile complexes (NONOates) (C. M. Maragos et al., Complexes of NO with nucleophiles as agents for the controlled biological release of nitric-oxide-vasorelaxant effects J. Med. Chem, 34, 3242, 1991). A number of functional groups are capable of complexing with NO, however most commonly NONOates are formed from primary and secondary amines (e.g. as described in U.S. Pat. No. 4,954,526) in which NO binds to the amine moiety, and preferably a secondary amine. These NONOates may also be known as diazeniumdiolates.
At present, the use of NONOates in therapy is limited because they become distributed throughout the body which may compromise selectivity. An additional issue is that many NONOates are inherently unstable, with short shelf lives even at high pH, and comparatively short half-lives in biological conditions (of the order of minutes).
None the less, some NONOates have shown promise as controlled release substances, for releasing nitric oxide triggered by changes in temperature, pH, exposure to water or by photoactivation.
(Aloka Srinivasan, Naod Kebede, Joseph E. Saavedra, Alexander V. Nikolaitchik, Daniel A. Brady, Emily Yourd, Keith M. Davies, Larry K. Keefer and John P. Toscano J. Am. Chem. Soc. 2001, 13; 123(23):5465-72) describe photoactivated release of NO from NONOates. However, potentially toxic (e.g. carcinogenic) products resulting from alternative decomposition pathways remain a concern.
Lehmann et al. Eur. J. Med. Chem., 19 Jan. 2005 reported the use of different diazeniumdiolates (NONOates) releasing NO. Among them a ciprofloxacin-diazeniumdiolate hybrid compound proven to release NO using a pH-temperature trigger. The NO liberation was reported only in aqueous buffer solution at pH 7.0-8.0, and the “burst effect” attributable to the trigger was relatively modest and of short half-life. Moreover, controlled release in this way from solution is unsuitable for many applications (e.g. wound dressing).
WO 2014/012074 describes NO-releasing coxib compounds (coxib compounds have use as anti-cancer agents) whereby different molecules containing a NO moiety deliver the gas through a metabolic pro-drug mechanism (i.e. class (b)).
The class (b) of molecules also include glyceryl trinitrate and sodium nitroprusside (L. J. Ignarro Biosynthesis and metabolism of endothelium-derived nitric-oxide Ann. Rev. Pharmacol. Toxicol. 30, 535, 1990). These compounds are currently widely used as vasodilators, however prolonged use can lead to toxic side products such as cyanides.
Furthermore, because the molecules in class (b) need to be metabolised to release NO, the targeting of NO to particular sites may also be poor resulting in the effects tending to be systemic.
In addition to certain diazeniumdiolates (NONOates), the class (c) includes metal complexes, such as the ruthenium complexes described by C. Works, C. J. Jocher, G. D. Bart, X. Bu, P. C. Ford, Photochemical Nitric Oxide Precursors Inorg. Chem., 41, 3728, 2002. Overall, however, the range of chemistries from which photoinitiated NO release is possible remains limited. Moreover, the small molecules and complexes left over after NO release typically perform no other function and may even be associated with longer-term toxicity issues.
Class (d) release of nitric oxide mitigates the problems associated with systemic activity by delivering nitric oxide to a specific target site by supporting a nitric oxide releasing compound on a solid article. Such NO releasing compounds may be polymeric materials which can be coated onto medical instruments which can be used to target specific areas of the body for treatment. The polymers may contain, for example, the N2O2 group that releases NO after a chemical reaction (International Patent Application WO 95/24908 and US Patent Application 2002094985). However, the release of NO in such circumstances can be difficult to control and currently the preparation of the required materials may be expensive. The possible use of such polymers has been shown in the treatment of cardiovascular problems, for example, restenosis.
Class (e) also mitigates the problems associated with systemic activity by releasing the nitric oxide from a crystalline metal-exchanged porous aluminosilicate porous framework material called a zeolite (as described in the applicant's earlier international patent application WO 2005/003032). The reported capacity of these materials is acceptable at about 1 mmol of NO per g of zeolite and the materials have been shown to have anti-thromobosis properties (Wheatley et al. Journal of the American Chemical Society, 128, 502-509, 2006).
Storage and release of NO from metal organic framework materials (MOFs) has also been reported, for example in the applicant's earlier international patent applications, nos. WO 2008/020218, WO 2012/020214 and WO 2013/186542. The use of MOFs for the storage and controlled release of NO is also reported by R. E. Morris and P. S. Wheatley, Angew. Chem. Int. Ed., 2008, 47, 4966, which reports exceptional performance in adsorption and release of NO over time from MOFs of CPO-27 structure, upon exposure to air and humidity.
Metal-organic frameworks (MOFs) are a class of nanoporous material. In these solids metal ions (Mn+) are linked together with organic units (Ly−) to form three dimensional networks. Many of these networks show good thermal stability and are extremely porous, with up to ˜90% free volume. (O. M. Yaghi et al. Nature, 423, 705, 2003 (b) H. Li et al Nature 402, 276, 1999. (c) WO200288148-A).
A number of readily available and potentially useful MOF materials do not exhibit this behaviour towards storage and release of NO, however. In addition, although release triggered by contact with water, or only triggered by contact with water, is ideal for certain applications, this behaviour may be unsuitable for other applications. Additionally, the requirement for the NO loaded MOFs to be stored in dry inert conditions may also be limiting.
There are some reports of NO-releasing molecules being used as linkers in MOFs and related materials. A. Lowe, P. Chittajallua, Q. Gongb, J. Lib, K. J. Balkus Jr. Micropor. Mesopor. Mat. 2013, 181 (17-22) and J. L. Nguyen, K. K. Tananbe, and S. M. Cohen, CrystEngComm 2010, 12, 2335-2338 have reported a MOF structure made with a linker containing secondary amines. These amino groups can be used as bonding sites for nitric oxide (in contrast to the metal sites, for example as described by Morris et al., mentioned above). The resulting framework NONOate groups are able to release NO over time when exposed to high levels of humidity, elevated temperature and/or a pH change, but the overall NO capacity of the materials so far reported is limited.
There are also reports of NO storage in other classes of porous materials. For example, S. Diring, K. Kamei and S. Furukawa Nature Communications 2013, 2684 (4) describe boron imidazole frameworks capable of NO release upon exposure to UV light. However, since the nitric oxide is part of the linker, NO release degrades the linker and thus the framework. The NO release is therefore irreversible.
B. J. Heilman, S.t R. J. Oliver, and P. K. Mascharak J. Am. Chem. Soc., 2012, 134 (28), pp 11573-11582 describes a manganese nitrosyl complex capable of photoactively releasing NO. The complex as a whole can be adsorbed into a porous material (e.g. AI-MCM-41), but this blocks the pores and prevents adsorption of any other molecules.
Accordingly, there remains a need for improved materials and compositions for the controlled release of antimicrobial agents, to address or mitigate one or more of the foregoing disadvantages.